Semi-synthetic puwainaphycin/minutissamide cyclic lipopeptides with improved antifungal activity and limited cytotoxicity

Abstract

Both the substitution of free hydroxyl substituents and extending/branching of the fatty acid moiety improved the antifungal potency and limits the cytotoxicity of cyanobacterial cyclic lipopeptides puwainaphycin/minutissamides.

Fatty Acid Substitutions Modulate the Cytotoxicity of Puwainaphycins/Minutissamides Isolated from the Baltic Sea Cyanobacterium Nodularia harveyana UHCC-0300

“…The anti-proliferative activity of PUW F, MIN A-D, and MIN E-L has been reported in the literature, with different experimental settings and on different human cell lines (HeLa, colon carcinoma HT-29, and melanoma cell MDA-MB 435, respectively). , Recently, the cytotoxic activity of PUW/MIN variants with respect to the length of the FA moiety was studied by our team, and it was concluded that in a certain FA length span (C 12 –C 14 ), the cytotoxicity increases with the FA length but reduces further with FA extension . We used identical setting of the experiment and performed the cytotoxicity assays on human HeLa cells.…”

“… 19 , 20 Recently, the cytotoxic activity of PUW/MIN variants with respect to the length of the FA moiety was studied by our team, and it was concluded that in a certain FA length span (C 12 –C 14 ), the cytotoxicity increases with the FA length but reduces further with FA extension. 26 We used identical setting of the experiment and performed the cytotoxicity assays on human HeLa cells. To obtain a broader picture, we included four PUW/MIN variants ( 14 – 17 ) previously isolated, differing in their amino acid positions 4–8 from the PUW/MIN variants isolated from N. harveyana strain UHCC-0300 ( Figure 3 ).…”

“… 20 Although non-substituted PUW/MIN variants were not subjected to the cytotoxicity test in this study, it is worthy to mention that PUW F bearing unsubstituted C 14 FA showed moderate IC 50 values against HeLa with an IC 50 value of 2.2 μM, 25 and MIN A with C 12 FA was reported to possess a similar potency against HT-29 and HeLa cells with IC 50 values of 2.0 μM 19 and 2.8 μM, respectively. 26 …”

“…Twenty-one variants have been reported so far with the structural diversity arising from the differences in their peptide core as well as the FA substitution of different lengths (C 10 –C 18 ) (Figure ). A wide range of bioactivities have been reported for PUW/MIN variants, including cardiovascular activity, anti-proliferative activity, and antifungal activity. ,− ,, PUW/MIN chemical variants are synthesized by a hybrid non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) pathway that is accompanied by a set of tailoring enzymes . PUW/MIN biosynthesis begins with fatty-acyl-AMP ligases (FAAL) that are responsible for the activation of FAs, which are subsequently elongated by type I PKS modules encoded by PuwB and PuwE proteins .…”

Comparative genomics of Bacillus cereus sensu lato spp. biocontrol strains in correlation to in-vitro phenotypes and plant pathogen antagonistic capacity

“…In contrast, several unique clusters, which may contribute to the specific antifungal activity of each Bcsl strain, were also detected. These include a BGC, only detected in the UW85 and LSTW-24 genomes, having similarity (21%–42%) for the NRPs-PKs hybrid locillomycin, reported to antagonize R. solani and F. oxysporum ( Luo, 2015 ) and a BGC found in S-10 and UW85 genomes with similarity (50–60%) to a puwainaphycin lipopeptide, which was previously shown to possess antifungal activity against members of the Ascomycota phylum ( Mares et al, 2019 ; Hajek et al, 2021 ). Interestingly, in our research we did not observe inhibition of F. oxysporum which represent the Ascomycetes soilborne pathogen, but this predicted gene cluster similar to puwainaphycin need to be further explored for its role in the inhibition activity of these two strains against R. solani and P. aphanidermatum .…”